Dry Powder Compositions for Intranasal Delivery

ABSTRACT

A pharmaceutical composition in a form of dry powder for intranasal administration includes solid particles of at least one active agent and solid particles of a diluent. The pharmaceutical composition is substantially free of excipients other than the solid diluent. The pharmaceutical composition has at least 90% of the particles of the at least one active agent with a mean particle size of 10-30 microns and less than 10% of the particles of the at least one active agent with a mean particle size equal to or below 5 microns. The particles of the diluent have a mean particle size of 30-200 microns. An apparatus and method for preparation of the pharmaceutical composition utilize a spray-drying chamber, a cyclone separator, and a receiving chamber.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/636,178 filed Feb. 3, 2020, which is a U.S. National Phase ofPCT/IL2018/050914 filed Aug. 19, 2018, which claims priority to U.S.provisional Application 62/547,858 filed Aug. 20, 2017. All applicationsare incorporated by reference herein in their entirety.

TECHNICAL FIELD

The present application relates to delivery of drugs by intranasaladministration of a pharmaceutical composition comprising at least oneactive agent and lactose or a lactose functional analogue as dry powderparticles of specific particle size. The present application furtherrelates to methods for the preparation of the pharmaceuticalcompositions and, more particularly, to methods of treatment of asubject in need thereof by administration of at least one pharmaceuticalactive agent via intranasal delivery to the uppermost region of thenasal cavity.

BACKGROUND

Intranasal delivery has a number of compelling advantages over otherroutes of administration, namely its non-invasiveness, rapid attainmentof therapeutically relevant concentrations to the bloodstream, nofirst-pass metabolism, and ease of administration. Viable nasal deliverytechnologies have the potential to enable drug developers in creatinginnovative medicines using already approved products by delivering themthrough new routes of administration.

The intranasal delivery of drugs utilizes devices of several types, suchas nebulizers, pressurized devices, dry powder sprayers, andbi-directional nasal devices. Dry powders are used in intranasal drugdelivery due to many advantages of using this dosage form including theimproved stability, administration of larger doses and lack of microbialgrowth (no need for preservatives). The administration of intranasalpowders may improve patient compliance, especially if the smell andtaste of the delivered composition comprising excipients is unpleasant.Compared to drug solutions, the administration of powders can result ina prolonged contact with the nasal mucosa. Powder form is suitable fordelivery of both small molecules and biologics, especially peptides,hormones and antibodies.

Traditionally, intranasal preparations have been used for localadministration of anti-histamines, decongestants and steroids, foralleviation of cold, allergy symptoms and/or nasal congestion. Morerecently, researchers' attention has been focused on two specific areas:

-   (1) The potential rapid drug absorption into the systemic    circulation provided by turbinate and lymphoid tissues located at    the back of the nasal cavity. This has already been in use in a    number of indications e.g. migraine and pain relief, osteoporosis,    vaccines, etc., and-   (2) The potential of the “Nose to Brain” (N2B) delivery to the    central nervous system (CNS) presented by the olfactory region at    the top of the nasal cavity, for the treatment of central nervous    system (CNS) diseases. Blood brain barrier (BBB) prevents the    treatment of neurological diseases by many potential drugs. Among    them are Alzheimer's, Parkinson's, stroke, spinal cord injury,    depression, and other CNS disorders. The blood-brain barrier is    related primarily to the endothelium of the brain capillaries,    through which few molecules can pass.

There are many advantages to the intranasal administration ofmedications that include, among others, a direct route to the bloodstream, avoidance of hepatic first pass metabolism, higherbioavailability, ease and convenience of non-invasive manipulation, andproximity to the central nervous system. In addition, direct delivery ofdrugs to the brain provides the possibility of a bettertherapeutic-toxic ratio than with systemic drug delivery.

The olfactory region inside the nasal cavity, involved in sensing odorsand chemicals, provides a unique and direct connection between the brainand the external environment. A number of studies reported drugs that donot or poorly cross the blood-brain barrier, but are rapidly deliveredto the CNS when delivered intranasally, preferably delivered directly tothe turbinate and lymphoid tissues located at the back of the nasalcavity. A free communication exists between the nasal submucosalinterstitial space and the olfactory perineuronal space, which iscontiguous with a subarachnoid extension that surroundings the olfactorynerve. The olfactory epithelium is capable of metabolizing some drugs.The olfactory neuronal pathway includes both the intracellular(intraneuronal) and extracellular (extraneuronal) pathway into thebrain. After reaching the olfactory bulb and/or trigeminal region theactives may enter into other brain regions by diffusion, which may alsobe facilitated by arterial pulsation. In addition, intranasallyadministered drugs may also partially enter into CNS after itspenetration into the systemic blood circulation.

Mostly hydrophilic drugs like dopamine and picolinic acid can betransported through the olfactory pathway. In case of lipophilic drugs,the systemic route is better than olfactory route because it can crossthe blood brain barrier (BBB). Sinagh et al showed that alprazolamloaded in solid-lipid nanoparticles was rapidly transferred to therabbit brain via intranasal route, bypassing the blood-brain barrier¹.The enhanced rate and extent of transport may help in reducing the doseand dosing frequency, thereby providing a better compliance forambulatory patients. Another study confirmed that intranasal oxytocinadministration could increase confidence in human subjects². ¹AlokPratap Singh, Shailendra K. Saraf, Shubhini A. Saraf. SLN approach fornose-to-brain delivery of alprazolam, Drug delivery and TranslationalResearch, 2012, vol. 2, Issue 6, pp 498-507²Kosfeld M, Heinrichs M, ZakP J, Fishbacher U, Fehr E: OxyContin increases trust in humans. Nature,2005, vol. 435, pp 637-676

Moreover, an increasing number of studies on both animals and humansubjects suggested that intranasal drug delivery could be used totransfer not only small molecules but also large sized biologics intothe CNS by bypassing the BBB. Benedict et al showed that insulinadministration by the intranasal route may improve memory and mood ofhealthy adults³. Freiherr et al⁴ and Reger et al⁵ demonstrated that thememory of AD patients may also be approved without altering blood levelsof insulin or glucose. Jin et al reported that intranasal administrationof either fibroblast growth factor-2 or heparin-binding epidermal growthfactor may have potential as neurogenesis-promoting therapeutic³Benedict C, Hallshmid M, Schultes B, Born J, Kern W; Intranasal insulinto improve memory function in humans. Neuroendocrinology, 2007, vol. 86,pp 136-142 agents⁶. All aforementioned pharmaceutical actives wereadministered to the nasal cavity as sprays.⁴Freiherr J et al.,Intranasal Insulin as a Treatment for Alzheimer's Disease: A Review ofBasic Research and Clinical Evidence, CNS Drugs 2013, vol. 27, pp505-514⁵Reger M A, Watson G S, Frey W H 2^(nd) et al., Effect ofintranasal insulin on cognition in memory impaired older adults:modulation by APOE genotype. Neurobiol. Aging, 2006, vol. 27, pp451-458⁶Kunlin Jin M D, David A. Greenberg et al, Cerebral neurogenesisis induced by intranasal administration of growth factors; Ann. Neurol.2003, vol. 53, pp 405-409

While intranasal delivery specifically to the olfactory regionpotentially provides a route for delivery of agents to the CNS, theolfactory region is difficult to access using conventional nasaldelivery devices. The olfactory region is located in the uppermostregion of the nasal cavity, where less than 10% of the inhaled airflows. Conventional nasal sprays deposit the majority of the drug in thelower region of the nasal cavity, with very little drug reaching theolfactory region. Improved devices for the spray delivery to theolfactory region are described in US Patent Application No. 20070119451.The devices include a nosepiece and an elongated tubular member slidablydisposed within the nosepiece for movement between a retracted positionand an extended position. The tubular member is in flow communicationwith a reservoir containing the substance to be delivered. During theuse, the tubular member extends from the device, to direct the substancetoward the olfactory region. However, this reference does not disclosedelivery of solid dry powders. Similar devices are disclosed in US20030178440, U.S. Pat. Nos. 6,866,039, 6,945,953 and US 20050028813.

U.S. Pat. No. 9,556,260 described methods and compositions for thetreatment of CNS disorders via intranasal administration of pooled humanimmunoglobulin G. As shown therein, intranasal administration allows thedirected delivery of intact IgG to the brain bypassing the need to passthrough the BBB. This results in greater efficiency for the treatmentand reduces the necessary IgG dose that must be administered to achievethe desired effect. Whilst pooled human IgG is isolated from donatedhuman plasma, pooled IgG is a limited resource. Therefore, if madepossible, the reduction in the effective dose of IgG would effectivelyincrease the therapeutic potential. Furthermore, intranasaladministration of IgG nearly eliminates the systemic exposure caused byintravenous administration, improving the overall safety profile of thetreatment. Also, it would be beneficial to intranasally administer IgGto the brain in the absence of permeability enhancers, some of which hasneuro-stimulation effects themselves.

US Patent Application No. 20140073562 relates to a nasal delivery deviceand method of delivering a substance, preferably comprising oxytocin,non-peptide agonists thereof and antagonists thereof, preferably as oneof a liquid, as a suspension or solution, or a powder to the nasalairway of a subject, preferably the posterior region of the nasalairway, and preferably the upper posterior region of the nasal airwaywhich includes the olfactory bulb and the trigeminal nerve, andpreferably in the treatment of neurological conditions and disorders.

U.S. Pat. No. 8,875,704 described a delivery device and method ofdelivering a powdered substance, in particular a triptan, such assumatriptan, to the posterior region of a nasal cavity of a subject, inparticular for the treatment of headaches, for example, clusterheadaches and migraine, and neuropathic pain. WO 2016133863 provides anasal powder formulation containing glucagon or a glucagon analog fornasal administration, useful in the treatment of hypoglycemia, and inparticular the treatment of severe hypoglycemia. Sherr et aldemonstrated in their clinical trials that glucagon nasal powderdelivering glucagon transmucosally might be a promising alternative tointramuscular glucagon in adults and youth with type 1 diabetes⁷.However, Sherr et al did not mention that glucagon can be delivered fromnose to brain. ⁷Jennifer L. Sherr et al, Glucagon Nasal Powder: APromising Alternative to Intramuscular Glucagon in Youth with Type 1Diabetes, Diabetes Care 2016; vol. 39, pp 555-562.

U.S. Pat. No. 6,462,090, US 20080292713, US 20150010633, US 20160354288and other similar publications described dry powder inhalers (DPI) oftherapeutic agents for pulmonary delivery. US 20150010633 disclosed thepreparation of aerosol formulations of ondansetron useful exclusivelyfor pulmonary delivery, because the active drug ondansetron, whenadministered by inhalation, must penetrate deep into the lungs in orderto show physiological action. However, none of the publications aboveteach or mention the delivery of therapeutic agents to the brain viaintranasal administration. Accordingly, there is an unmet need formethods of treating central nervous system (CNS) disorders with knownand new active agents that provide specific targeting to the CNS (interms of direct administration primarily to the brain), reduce systemicdistribution of the active agents and lower the therapeutically effecteddoses needed for administration.

SUMMARY

The present application describes embodiments of a pharmaceuticalcomposition in a form of dry powder for intranasal administration,comprising solid particles of at least one active agent and solidparticles of a diluent, said pharmaceutical composition beingsubstantially free of excipients other than the solid diluent, whereinsaid pharmaceutical composition having at least 90% of the particles ofsaid at least one active agent with a mean particle size of 10-30microns and less than 10% of the particles of said at least one activeagent with a mean particle size equal to or below 5 microns, and havingthe particles of said diluent with a mean particle size of 50-200microns.

The pharmaceutical composition of the embodiments of the presentapplication comprises at least one hydrophilic active agent forintranasal delivery selected from analgesics, anti-emetics,anti-inflammatory agents, anti-bacterial agents, anti-viral agents,anti-depressants, anti-epileptics, anti-hypertensive agents,anti-migraine agents, anti-neoplastic agents, chemotherapeutic drugs,immunosuppressants, anti-Parkinsonian agents, anxiolytic agents,sedatives, hypnotics, neuroleptics, beta-blockers, corticosteroids,COX-2 inhibitors, opioid analgesics, protease inhibitors, hormones,peptides, antibodies, chemotherapy agents and mixtures thereof.

In some embodiments, the hydrophilic active agent may be selected fromsumatriptan succinate, zolmitriptan salts, naratriptan, rizatriptan,almotriptan, eletriptan, frovatriptan, bupivacaine, fibroblast growthfactor, cephalexin, lidocaine, clobazame, midazolam, alprazolam,diazepine, lorazepam, dexmedetomidine, monosialoganglioside, cocaine,insulin, glucagon, oxytocin, fentanyl, sulfentanil, diamorphine,ketamine, apomorphine, buprenorphine, morphine sulphate, oxycodonehydrochloride, butorphanol, NSAIDs, paracetamol, benzodiazepines,dopamine, pramipexole, rasagiline, rogitine, ondansetron, granisetron,metoclopramide, naloxone and naltrexone, atropine, epinephrine,isosorbide dinitrate, obitoxine, dexmedetomidine, metochlorpramide,L-dopa, nicotine, sildenafil, nafarelin, dobutamine, phenylephrine,tramazoline, xylometazoline, tramadol, methacholine, ipratropium,scopolamine, propranolol, verapamil, hydralazine, nitroglycerin,clofilium tosylatecannabis active compounds and pharmaceuticallyacceptable salts, isomers, and mixtures thereof.

In other embodiments, the pharmaceutical composition contains anacceptable diluent selected from lactose monohydrate, lactose, dextrose,sorbitol, mannitol, maltitol, xylitol or mixtures thereof.

The pharmaceutical composition of the embodiments is prepared by amodified spray drying method. An apparatus for the preparation of thepharmaceutical composition in the dry powder form of the embodimentscomprises the following components:

-   a) A spray-drying chamber capable of spray-drying a clear and    homogeneous solution of at least one active agent to obtain dry    powder particles of said at least one active agent in a moist air,    said solution being free of diluent;-   b) A cyclone separator capable of receiving said dry powder    particles and the moist air stream from said spray-drying chamber,    separating said particles from the moist air through vortex    separation, exhausting the air and transferring the separated    particles to a receiving chamber through a bag filter; and-   c) The receiving chamber pre-filled with a diluent and adapted for    receiving the separated dry powder particles from the cyclone    separator, stirring and homogenising said particles with the diluent    to obtain the pharmaceutical composition in the dry powder form of    the embodiments; wherein said diluent is capable of colliding and    continuous in-situ blending with the particles during the stirring    in the receiving chamber, thereby preventing their aggregation and    preserving their original size and shape.

The spray-drying chamber is equipped with nozzles, which are used toproduce droplets of the active agent solution, to control the dropletand powder particle size and to maximise heat transfer and the rate ofsolvent vaporisation. The droplet size may range from 20 to 180 μm,depending on a particular nozzle used. In the present embodiments, thesprayed solution of the active agent is free of any diluent. The nozzlesare designed to spray the solution of the active agent into a hot airflow, thereby achieving a thorough mixing and uniform distribution ofthe hot air flow and sprayed solution in the spray-drying chamber toproduce a substantially complete evaporation of liquids and drying ofsolid particles of the active agent from the mixture throughout saidchamber.

At the laboratory scale, the stirring and homogenisation is achieved byusing a magnetic stirrer and a magnetic bar of appropriate size, inaddition to the rotation of the receiving chamber. At industrial scale,the stirring and homogenisation may be achieved by using a mechanicalstirrer of appropriate size and form, or moving, rotation and vibrationof the whole receiving chamber. A conventional spray-drying apparatuscontains the empty receiving chamber collecting the dry powder particlesof an active agent. This receiver is emptied from time to time in orderto ensure the continuous process. In contrast, the present applicationdiscloses the receiving chamber pre-filled with a continuously stirreddiluent for preventing aggregation of the dry powder particles andpreserving their original size and shape.

The pharmaceutical composition of the embodiments contains a diluentadded to the dry powder particles of the active agent after theirspray-drying. In contrast, various pharmaceutical compositions describedin the literature and processes commonly utilised for preparation ofinhalable powders use surfactants and lipid agents for prevention of theparticles aggregation and for the powder disaggregation andde-agglomeration. The use of a solid diluent, such as lactose or lactosefunctional analogues, having particles larger than the particles of theactive agent, for the preparation of the inhalable dry powderformulation has never been mentioned in the literature.

In further embodiments, a method for the preparation of thepharmaceutical composition of the present application, comprises thefollowing steps:

-   A. Preparing a clear and homogeneous solution of at least one active    agent in an organic solvent or solvent mixture, in a solvent-water    or water miscible solvent mixture, or in water.-   B. Filling the receiving chamber with a diluent and continuously    stirring the diluent in the receiving chamber;-   C. Streaming the solution prepared in step (A) together with hot air    or gas to the spray-draying chamber, spray-drying the solution in    the spray-drying chamber to obtain dry powder particles of said at    least one active agent in a moist air or gas, and transferring the    obtained dry powder particles and the moist air or gas stream to the    cyclone separator;-   D. Separating said particles from the moist air or gas through    vortex separation in the cyclone separator, exhausting the air or    gas and transferring the separated particles to the receiving    chamber through a bag filter;-   E. Stirring and homogenising said particles received from step (D)    with the diluent in the receiving chamber to obtain the    pharmaceutical composition of the embodiments in the dry powder    form; wherein said diluent is capable of colliding and continuous    in-situ blending with the particles during the stirring in the    receiving chamber, thereby preventing their aggregation and    preserving their original size and shape; and-   F. Additional mixing of the pharmaceutical composition obtained    in (E) with an additional amount of the diluent to achieve the    desired active agent-to-diluent ratio in said pharmaceutical    composition.

In other embodiments, the clear and homogeneous solution of the activeagent is obtained by dissolving the active agent either as a free baseor as a salt in an organic solvent, a mixture of two or more organicsolvents or in water. In particular embodiments, the pharmaceuticalcomposition comprising the active agent may further comprise one or morepharmaceutically acceptable diluents, excipients or mixtures thereof. Insome other embodiments, the pharmaceutical composition may be preparedin a form of a powder, simple powder mixtures, powder microspheres,coated powder microspheres, liposomal dispersions and combinationsthereof.

Thus, the pharmaceutical composition of the embodiments may comprise atleast one active agent and a diluent selected from the group consistingof lactose, lactose monohydrate, cellulose and derivatives, starch andderivatives, dextrose, sorbitol, mannitol, maltitol, xylitol or mixturesthereof. In some particular embodiments, the composition may be free ofany other excipient than the diluent.

Active agents for intranasal inhalation in the dry powder form areusually produced by milling techniques. As a result, their particle sizedistribution is broad and their particle shapes are non-spherical andnon-uniform. The active agent particles of less than 5 microns (μm)should however be avoided. They may reach the lungs mucosa by nasalspraying with a nasal spraying device or by inhaling with an inhalationdevice. This is completely unacceptable for intranasal administrationfrom the safety point of view. Therefore, the production of thespherical-shape particles with the narrow particle size distributionlarger than 5 μm and their use in nasal spraying and inhalation devicesare beneficial for the intranasal administration. In yet furtherembodiments, the present application provides a process for obtainingdry powder particles of a spherical shape with a narrow particle sizedistribution by spray-drying a solution of at least one active agentfree of diluent, and mixing the obtained dry powder particles of the atleast one active agent with a diluent in the receiving chamber of thespray-drying apparatus under continuous stirring. In some embodiments,the pharmaceutical composition of the embodiments may be administered inan intranasal or oral solid dosage form.

Clear superiority of the intranasal composition of the present inventionto the brain and plasma is shown in the in-vivo experiments.

Various embodiments may allow various benefits, and may be used inconjunction with various applications. The details of one or moreembodiments are set forth in the accompanying figures and thedescription below. Other features, objects and advantages of thedescribed techniques will be apparent from the description and drawingsand from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Disclosed embodiments will be understood and appreciated more fully fromthe following detailed description taken in conjunction with theappended figures:

FIG. 1 shows the Scanning Electron Microscopy (SEM) image of sumatriptansuccinate agglomerated powder, when the receiving chamber is empty (notprefilled with a diluent or disaggregation agent).

FIG. 2 shows the schematic drawing of the modified spray-dryer apparatusof the embodiments, suitable for the particles engineering andprevention of agglomeration.

FIGS. 3 and 4 show the SEM images of lactose monohydrate (large cubicparticles or tomohawks comprising “C” and “0” elements) and sumatriptansuccinate particles (small spherical particles comprising also “S”element) of dry powder for intranasal delivery formulation.

FIG. 5 shows the particle size distribution of the pharmaceuticalcomposition of the embodimens (see Example 3). Two populations of theparticles are clearly seen: the acive agent (API) in the range of 5-25microns (μm) and lactose in the range of 50-200 microns; D(10)=11.6 μm;D(50)=95.4 μm; D(90)=155 μm.

FIG. 6 shows the particle size distribution of the API in thepharmaceutical composition of the embodiments (see Example 3). The meanparticles size is 12 μm.

FIG. 7 shows the SEM image (×100) of the mixture of lactose monohydrate(large polyhedrons) and alprazolam in the dry powder composition of theembodiments for intranasal administration.

FIG. 8a shows the SEM image (×1200) of lactose monohydrate (largepolyhedrons) and alprazolam (small polyhedrons) of the dry powdercomposition of the embodiments for nasal administration formulation.

FIG. 8b shows the X-ray elemental analysis of the large polyhedronsconfirming that these are the particles of lactose monohydratecontaining “C” and “0” atoms. FIG. 8c shows the X-ray elemental analysisof the small polyhedrons confirming that these are the particles ofalprazolam containing “C”, “0” and “Cl” atoms.

FIG. 9 shows the SEM images (×600) of the mixture of lactose monohydrate(large polyhedrons) and oxicodone hydrochloride (small non-aggregatedspheres) in the dry powder composition of the embodiments for intranasaladministration.

FIG. 10 shows the particle size distribution of the pharmaceuticalcomposition of the embodiments (see Example 14). Two populations ofparticles is clearly seen: oxicodone hydrochloride in the range of 3-30μm and lactose in the range of 50-200 μm. D(10)=57.4 μm; D(50)=97.3 μm;D(90)=151 μm;

FIG. 11 shows the SEM image (×2400) of lactose monohydrate (largepolyhedrons) (Particle 1) and insulin-sodium chloride (small sphericalshape) (Particles 2, 3, 4 and 5) of the dry powder composition forintranasal administration.

FIG. 12 shows the X-ray elemental analysis of Particle 2 containing “C”,“0” and “S” atoms of insulin molecules and “Na” and “Cl” atoms of thesodium chloride salt.

FIG. 13 shows the particle size distribution of the pharmaceuticalcomposition of the embodiments (see Example 19). Two populations of theparticles are clearly seen: insulin-sodium chloride particles in therange of 5-35 μm and lactose in the range of 50-200 μm. D(10)=57.4 μm;D(50)=97.3 μm; D(90)=151 μm.

FIG. 14 shows the oxycodone pharmacokinetic profiles in rat's plasmafollowing administration of oral gavage (oral) and intranasal powder(intranasal) to 12 SD rats at dose of 10 mg/kg.

FIG. 15 shows the oxycodone pharmacokinetic profiles in rat's brainsfollowing administration of oral gavage (oral) and intranasal powder(intranasal) to 12 SD rats at dose of 10 mg/kg.

DETAILED DESCRIPTION

In the following description, various aspects of the present applicationwill be described. For purposes of explanation, specific configurationsand details are set forth in order to provide a thorough understandingof the present application. However, it will also be apparent to oneskilled in the art that the present application may be practiced withoutthe specific details presented herein. Furthermore, well-known featuresmay be omitted or simplified in order not to obscure the presentapplication.

The terminology used herein is for describing particular embodimentsonly and is not intended to be limiting of the invention. The term“comprising” and “comprises”, used in the claims, should not beinterpreted as being restricted to the components and steps listedthereafter; they do not exclude other components or steps. They need tobe interpreted as specifying the presence of the stated features,integers, steps and/or components as referred to, but does not precludethe presence and/or addition of one or more other features, integers,steps or components, or groups thereof. Thus, the scope of theexpression “a composition comprising A and B” should not be limited tocompositions consisting only of components A and B. Also, the scope ofthe expression “a method comprising the steps X and Z” should not belimited to methods consisting exclusively of those steps.

Unless specifically stated, as used herein, the term “about” isunderstood as within a range of normal tolerance in the art, for examplewithin two standard deviations of the mean. In one embodiment, the term“about” means within 10% of the reported numerical value of the numberwith which it is being used, preferably within 5% of the reportednumerical value. For example, the term “about” can be immediatelyunderstood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. In other embodiments, theterm “about” can mean a higher tolerance of variation depending on forinstance the experimental technique used. Said variations of a specifiedvalue are understood by the skilled person and are within the context ofthe present invention. As an illustration, a numerical range of “about 1to about 5” should be interpreted to include not only the explicitlyrecited values of about 1 to about 5, but also include individual valuesand sub-ranges within the indicated range. Thus, included in thisnumerical range are individual values such as 2, 3, and 4 andsub-ranges, for example from 1-3, from 2-4, and from 3-5, as well as 1,2, 3, 4, 5, or 6, individually. This same principle applies to rangesreciting only one numerical value as a minimum or a maximum. Unlessotherwise clear from context, all numerical values provided herein aremodified by the term “about”. Other similar terms, such as“substantially”, “generally”, “up to” and the like are to be construedas modifying a term or value such that it is not an absolute. Such termswill be defined by the circumstances and the terms that they modify asthose terms are understood by those of skilled in the art. Thisincludes, at very least, the degree of expected experimental error,technical error and instrumental error for a given experiment, techniqueor an instrument used to measure a value.

As used herein, the term “and/or” includes any combinations of one ormore of the associated listed items. Unless otherwise defined, all terms(including technical and scientific terms) used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs. It will be further understood that terms,such as those defined in commonly used dictionaries, should beinterpreted as having a meaning that is consistent with their meaning inthe context of the specification and relevant art and should not beinterpreted in an idealized or overly formal sense unless expressly sodefined herein. Well-known functions or constructions may not bedescribed in detail for brevity and/or clarity.

It will be understood that when an element is referred to as being “on”,“attached to”, “connected to”, “coupled with”, “contacting”, etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on”, “directly attached to”, “directly connectedto”, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” another feature may have portions thatoverlap or underlie the adjacent feature.

The terms “active agent”, “pharmaceutical active agent”, “active”,“API”, “active pharmaceutical ingredient”, “active substance”, “activemolecule”, “active compound” or “drug” are used interchangeably.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealised or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

In one embodiment, a pharmaceutical composition in a form of dry powderfor intranasal (nose-to-brain) N2B administration to a patient in needthereof comprises solid particles of at least one active agent and solidparticles of a diluent, said pharmaceutical composition beingsubstantially free of excipients other than the solid diluent, whereinsaid pharmaceutical composition having at least 90% of the particles ofsaid at least one active agent with a mean particle size of 10-30microns and less than 10% of the particles of said at least one activeagent with a mean particle size equal to or below 5 microns, and havingthe particles of said diluent with a mean particle size of 50-200microns.

The composition of the embodiment is essentially free of any excipientsother than the solid diluent, such as lactose monohydrate or a lactosefunctional analogue. In another embodiment, a pharmaceutical compositionin a form of dry powder for intranasal administration by transmucosalsystemic delivery via the upper nose mucosa (the turbinate and lymphoidtissues located at the back of the nasal cavity) of a compositioncomprises an active agent having a mean particle size in the range of10-30 microns, wherein at least 90% of its particles have a meanparticles size of not less than 5 microns and not more than 30 microns,and a diluent having a mean particle size in the range of 50-200microns. As noted above, the diluent is also used for preventingaggregation of the dry powder particles containing at least one activeagent.

At first sight, it would seem that the larger particle size might leadto a relatively lower N2B bioavailability of the active agent. However,this is offset by the better absorption of the larger particles of theactive agent in the present invention, due to the longer residence timeof the active on the nasal mucosa. Thus, a double advantage is obtainedby administration of the dry powder composition of this specificparticle size range: on one hand, better absorption of the active agent,and on the other hand, this mode of administration using delivery ofrelatively large particles directly to the upper region of the nasalcavity is substantially free of systemic effects due to lung delivery.In a further embodiment, the pharmaceutical composition for intranasalN2B administration comprises an active agent having a particle size inthe range from about 10 microns to about 30 microns, and more than 90%particles of the active agent are above 5 microns, and wherein theactive agent is delivered to the superior region of the nasal cavity. Inyet further embodiment, the composition comprises an active agent havinga mean particle size range of 10-30 microns, wherein at least 90% of itsparticles have a mean particles size of not less than 5 microns and notmore than 30 microns, and a diluent with a particle size in the range of50-200 microns, said composition may be administered either bynose-to-brain (N2B) delivery or by systemic delivery, or both.

In some embodiment, the intranasal delivery method of the presentapplication provides delivery of dry powders to the nasal mucosa,olfactory region, the trigeminal nerve and other structures of thelimbic system. In another embodiment, the pharmaceutical composition isused to deliver the active agent to the upper region of the nasalcavities. This upper region represents the only region where it ispossible to circumvent the blood-to-brain barrier and enable transportto the cerebrospinal fluid (CSF) and the brain.

The composition of the embodiments may be delivered by any one of theknown in the art nasal devices, such as pressurised devices, dry powdersprayers or bi-directional nasal devices. Multi-dose devices as well assingle-dose devices may be used.

In some embodiments, the desired attributes for an intranasal powderformulation with commercial potential required in EMA and FDAGuidelines⁸ are inherent features of the compositions of theembodiments. The uniform dose deliverability of the initial and storedformulation by a device for intranasal administration is exemplified inExample 22. None of the dose measurements was found to be outside75-125% of the label claim. ⁸EMA Guideline: Guideline on thePharmaceutical Quality of Inhalation and Nasal Products (June 2006); FDAGuidance for Industry (Chemistry, Manufacturing & ControlsDocumentation): Metered-Dose Inhaler (MDI) & Dry Powder Inhaler (DPI)Drug Products (October 1998).

The present application provides an apparatus and a method for themanufacture of a pharmaceutical composition in a form of dry powder forintranasal delivery having less than 5% of small particles below 5microns, to exclude undesirable administration to the lungs. FIG. 2schematically shows the apparatus for the preparation of thepharmaceutical composition of the embodiments in a dry powder form, saidapparatus comprises the following components:

-   a) A spray-drying chamber [1] capable of spray-drying a clear and    homogeneous solution of at least one active agent to obtain dry    powder particles of said at least one active agent in a moist air,    said solution being free of diluent;-   b) A cyclone separator [2] capable of receiving said dry powder    particles and the moist air stream from said spray-drying chamber    [1], separating said particles from the moist air through vortex    separation, exhausting the air and transferring the separated    particles to a receiving chamber [3] through a bag filter; and-   c) The receiving chamber [3] (or “receiver”) pre-filled with a    diluent and adapted for receiving the separated dry powder particles    from the cyclone separator [2], mechanically stirring and    homogenising said particles with the diluent to obtain the    pharmaceutical composition in the dry powder form of the    embodiments; wherein said diluent is capable of colliding and    continuous in-situ blending with the particles during the stirring    in the receiving chamber [3], thereby preventing their aggregation    and preserving their original size and shape.

The spray-drying chamber is equipped with nozzles, which are used toproduce droplets of the active agent solution, to control the dropletand powder particle size and to maximise heat transfer and the rate ofsolvent vaporisation. The spray-dryer apparatus of the embodiments thusreceives a stream of the liquid solution containing the active agent,sprays it through the nozzles into a hot gas stream, such as nitrogen orair, and removes the solvent as a vapor. As the moisture quickly leavesthe droplets, the dry powder is produced. The droplet size may rangefrom 20 to 180 μm, depending on a particular nozzle used. In the presentembodiments, the sprayed solution of the active agent is free of anydiluent.

The nozzles are designed to spray the solution of the active agent intoa hot air flow, thereby achieving a thorough mixing and uniformdistribution of the hot air flow and sprayed solution in thespray-drying chamber to produce a substantially complete evaporation ofliquids and drying of solid particles of the active agent from themixture throughout said chamber. In a specific embodiment, thespray-drying chamber is equipped with a two-fluid nozzle having anappropriate opening controlling the API particles size in the range of10-30 μm. One of the fluids is an active agent solution, free of anydiluent, and the other fluid is a drying gas or air.

At the laboratory scale, the stirring and homogenisation is achieved byusing a magnetic stirrer and a magnetic bar of appropriate size, inaddition to the rotation of the receiving chamber. At industrial scale,the stirring and homogenisation may be achieved by using a mechanicalstirrer of appropriate size and form, or moving, rotation and vibrationof the whole receiving chamber. A conventional spray-drying apparatuscontains the empty receiving chamber collecting the dry powder particlesof an active agent. This receiver is emptied from time to time in orderto ensure the continuous process. In contrast, the present applicationdiscloses the receiving chamber pre-filled with a continuously stirreddiluent for preventing aggregation of the dry powder particles andpreserving their original size and shape.

The method for the preparation of the pharmaceutical composition of theembodiments in a dry powder form is based on the spray-drying processrapidly drying the solution of at least one active agent, free of anydiluent or excipient, with hot air, thereby producing a dry powder ofthe active agent. This method comprises the following steps:

-   A. Preparing a clear and homogeneous solution of at least one active    agent in an organic solvent or solvent mixture, in a solvent-water    or water miscible solvent mixture, or in water.-   B. Filling the receiving chamber with a diluent and continuously    stirring the diluent in the receiving chamber;-   C. Streaming the solution prepared in step (A) together with hot gas    to the spray-draying chamber, spray-drying the solution in the    spray-drying chamber to obtain dry powder particles of said at least    one active agent in a moist gas, and transferring the obtained dry    powder particles and the moist gas stream to the cyclone separator;-   D. Separating said particles from the moist gas through vortex    separation in the cyclone separator, exhausting the gas and    transferring the separated particles to the receiving chamber    through a bag filter;-   E. Stirring and homogenising said particles received from step (D)    with the diluent in the receiving chamber to obtain the    pharmaceutical composition of the embodiments in the dry powder    form; wherein said diluent is capable of colliding and continuous    in-situ blending with the particles during the stirring in the    receiving chamber, thereby preventing their aggregation and    preserving their original size and shape; and-   F. Adding diluent and additionally mixing of the pharmaceutical    composition obtained in step (E) with the additional amount of the    diluent to achieve the desired active agent-to-diluent ratio in said    pharmaceutical composition.

The gas used in the spray-drying process is normally air. However, ifthe solvent is flammable, for example ethanol, or the product isoxygen-sensitive, then nitrogen or any other suitable inert gas may beused instead.

In a particular embodiment, the clear and homogeneous solution of theactive agent is obtained by dissolving an active agent either as a freebase or as a salt in an organic solvent, a mixture of two or moreorganic solvents or in water. The gas outlet temperature in the methodof the embodiments is generally about 75° C. or below, preferably about70° C. or below, more preferably about 59° C. or below, yet morepreferably about 52° C. or below, or about 50° C. The gas inlettemperature is generally about 75° C. or higher, preferably about 80° C.or higher, more preferably about 90° C. or higher, yet more preferablyabout 100° C. or higher, even more preferably about 110° C. or higher,or about 120° C. The volatile products obtained in the process are theorganic solvents and/or water. The volume of water should be 50% or moreof the volume of the volatiles. In the specific embodiment, a Class 3organic solvent is used in the method for the preparation of thepharmaceutical composition in a dry powder form. The residual solventcontent after drying is less than 0.5%.

The drug (active agent) content of the composition of the embodimentsmay be adjusted so as to provide the total dose of the drug required toachieve the therapeutic effect as a single dose in a single nostril. Thedrug administration can be repeated in the second nostril in order todouble the amount of the active material. Stability of the compositionof the embodiments on storage was determined under accelerated andambient conditions.

The device used for the intranasal delivery of the compositions of theembodiments may be engineered so as to provide the appropriate plumegeometry and spray pattern of initial and stored compositions. In someembodiments, these compositions may have a narrow particle sizedistribution with median diameter between 10 to 20 microns.

The shape and particle morphology of the dry powder of the embodimentsfor intranasal delivery were characterized using an electron microscope.Reference is now made to FIGS. 8a-8c and Example 13 (in the experimentalsection below) showing the polyhedron shape of the particles. FIGS. 3,4, 9 and 11 show spherical particles, contribution of which may be moresignificant in reaching the deeper region of the nasal passage.

The process of the embodiments for the preparation of the pharmaceuticalcomposition of the present embodiments in a dry powder form for nasaldelivery produces preponderantly a spherical population of particles. Inrare cases, the active agent may form a polyhedron-shape crystallineparticles or spherical/polyhedron mixtures.

Many previous attempts at developing an intranasal powder formulationfell short in one or several of the desired properties includingsatisfactory safety and tolerability profile. The compositions of theembodiments are designed to have some or all of these desiredproperties. These compositions have two required components:

(a) The active agent may be hydrophilic or lipophilic active agent,wherein the hydrophilic active ingredient may be delivered via olfactorymucosa to the brain and the lipophilic active agent may be delivered vianasal mucosa to systemic circulation and then to the brain, by-passingthe liver.(b) Lactose monohydrate or a lactose monohydrate functional analoguealso used for preventing aggregation of the active agent particles andpreserving their original size and shape.

The active agent of the embodiments is a hydrophilic or lipophilic,chemical or biochemical, solid therapeutic substance selected fromcompounds for use in common cold treatment, anti-addiction agents,anti-infective agents, analgesics, anaesthetics, anorexics,antarthritics, anti-allergy agents, antiasthmatic agents,anticonvulsants, anti-depressants, antidiabetic agents,anti-depressants, anti-diuretics, anti-emetics, antihistamines,anti-hypertensive agents, anti-inflammatory agents, antimigrainepreparations, anti-motion sickness preparations, antinauseants,antineoplastics, anti-obesity, antiosteoporosis, anti-Parkinsonismdrugs, antipruritics, antipsychotics, antipyretics, anticholinergics,benzodiazepine antagonists, bone stimulating agents, central nervoussystem stimulants, hormones, hypnotics, immunosuppressives,prostaglandins, proteins, peptides, polypeptides and othermacromolecules, psychostimulants, compounds for use in rhinitistreatment, compounds for use in sexual hypofunction treatment,sedatives, compounds for use in treatment of known or suspected opioidoverdose, tranquilizers and vitamins, probiotics, natural ingredients,peptide or protein therapeutic agents such as cytokines, hormones,clotting factors, vaccines, monoclonal antibodies, amino acids, or anycombination thereof.

In some embodiments, the active agent is selected from sumatriptansuccinate, zolmitriptan salts, naratriptan, rizatriptan, almotriptan,eletriptan, frovatriptan, bupivacaine, fibroblast growth factor,cephalexin, lidocaine, clobazame, midazolam, alprazolam, diazepine,lorazepam, dexmedetomidine, monosialoganglioside, cocaine, insulin,glucagon, oxytocin, fentanyl, sulfentanil, diamorphine, ketamine,apomorphine, buprenorphine, morphine sulphate, oxycodone hydrochloride,butorphanol, NSAIDs, paracetamol, benzodiazepines, dopamine,pramipexole, rasagiline, rogitine, ondansetron, granisetron,metoclopramide, naloxone, naltrexone, atropine, adrenaline, cannabisactive compounds, epinephrine, isosorbide dinitrate, obitoxine,dexmedetomidine, metochlorpramide, L-dopa, nicotine, sildenafil,nafarelin, dobutarnine, phenylephrine, tramazoline, xylometazoline,tramadol, methacholine, ipratropium, scopolamine, propranolol,verapamil, hydralazine, nitroglycerin, clofilium tosylatecannabis activecompounds and pharmaceutically acceptable salts, isomers, and mixturesthereof.

In a specific embodiment, the dry powder of the active agent for nasaldelivery contains at least 90% of the particles having a mean particlesize of 10-30 microns, and less than 10% of the particles having a meanparticle size equal to or below 5 microns. The particle size is measuredusing the laser diffraction method. The active agent particles may havespherical, ellipsoid, polyhedron, cubic, plate, or needle shapes. Thepreferable particle shapes are spherical and ellipsoid. These shapesprovide the best aerodynamic properties of the active agents. The drugparticle shape and morphology is determined using the electronmicroscopy.

The solid diluent of the embodiments is selected from lactosemonohydrate or a lactose monohydrate functional analogue, such aslactose, cellulose and derivatives, starch and derivatives, dextrose,sorbitol, mannitol, maltitol, xylitol or mixtures thereof. The preferredsolid diluent is lactose monohydrate.

Lactose may be present in the form of α-lactose monohydrate, anhydrousβ-lactose or amorphous lactose. α-Lactose monohydrate is a commonly usedDPI (dry powder inhaler) excipient, and is a pharmacopeia excipient forDPIs in a pulmonary delivery route. Lactose monohydrate of theembodiments has a bulk density of 0.6-0.8 g/ml and partlytomahawk-shaped crystals with the following particle size distribution:D₁₀ 30-60 μm; D₅₀ 70-110 μm and D₉₀ 110-150 μm.

According to Jagdeep Shur et al, “From single excipients to dualexcipient platform in dry powder inhaler products”, InternationalJournal of Pharmaceutics (2016), 514, pages 374-383, the singleexcipient platform (SEP) has been the most prevalent excipient strategyused in many commercial DPI products. The majority of approved SEP DPIproducts have been developed based on the well-known ‘carrier’ approach.The role, or functionality, of the single excipient in the SEP-based DPIproducts has traditionally been described as a ‘dispersant’, ‘filler’,‘diluent’ or ‘carrier’. The ‘carrier’ description is now so commonplacein academic, industrial and regulatory circles that in 2014 it wasincorporated into the updated respiratory section of the United StatesPharmacopoeia (General chapter 1059). Such ‘carrier’ excipients, oftenof a small particle size, are also used in what are described as‘agglomerate’ formulations. This is in contrast to the large particlesize (50-200 microns) of lactose or lactose functional analogue of theembodiments. Thus, unlike the regular DPIs, the excipient of theembodiments (such as lactose or lactose functional analogue) has ratherlarge particle size (50-200 microns), and—while being multi-functional,it is mainly used as a diluent and carrier for preventing agglomerationof much smaller particles of an active agent, deagglomeration of theparticles and homogenisation of the composition. Therefore, theexcipient of the embodiments is referred to throughout the presentapplication as “diluent”.

It is a surprising and unexpected finding that the lactose monohydratesolid diluent of the embodiments may serve for preventing aggregation oragglomeration of the active agent particles, or as a disaggregant orde-agglomerating agent in the preparation of the dry powder compositionfor intranasal administration, when the spray-dried active agent and thediluent are mixed in-situ in the receiving chamber of the spray-dryingapparatus. It is indeed unpredictable and surprising that the largeparticles of lactose monohydrate with a mean diameter of 50-200 μm arecapable of preventing the aggregation of the small active agentparticles with a mean diameter of 10-30 μm. The lactose monohydrateparticles cannot therefore enter the nasal passage and become swallowedafter actuation.

Thus, the compositions of the embodiments comprise at least one activeagent and a diluent, such as lactose or a lactose functional analogue,and are substantially free of other excipients, such as surfactants,lipid agents, solvents or propellants. Most of the DPI formulations relyon lactose monohydrate as a diluent. However, lactose cannot be used inthe compositions comprising active compounds that interact with thereducing sugar function of lactose in the Maillard reaction. Lactosefunctional analogues of the embodiments, which may be used as a soliddiluent instead of lactose and may replace lactose in some compositions,particularly as an alternative for patients suffering from lactoseintolerance, are selected from cellulose and derivatives, starch andderivatives, mannitol, glucose, sorbitol, maltitol, xylitol or mixturesthereof. The particle size of these diluents is also in the 50-200 μmrange.

The pharmaceutical composition of the embodiments may further compriseone or more pharmaceutically acceptable diluents, excipients or both.The pharmaceutical composition of the embodiments may be prepared in theform of a powder, simple powder mixtures, powder microspheres, coatedpowder microspheres, liposomal dispersions or combinations thereof.

The conventional spray drying process uses an empty receiving chamber inthe beginning of the process. Such receiving chamber is filled with thespray-dried product powder and emptied from time to time in order toensure the continuous process. In the present embodiments, the receivingchamber is however pre-filled with the continuously stirred diluent forpreventing agglomeration or de-agglomeration of the active agentparticles. The regular methods for the preparation of dry powders fornasal delivery usually use surfactants and lipid agents fordisaggregation and de-agglomeration of the solid particles and forpreventing their aggregation. It was surprisingly and unexpectedly foundthat rather coarse particles of the diluent, such as lactose or lactosefunctional analogue, with the size range of 50-100 μm preventaggregation of the active agent particles having the size range of 10-30μm. In a further embodiment, a method for disaggregation andde-agglomeration of the active agent dry powder and for preventing itssolid particles aggregation comprises in-situ mechanical mixing of theagent dry powder with a diluent, preferably lactose monohydrate, in thereceiving chamber of the spray-drying apparatus of the embodiments.

The active agent for nasal inhalation in a dry powder form is usuallyproduced by jet or wet milling techniques that give rise to broadparticle size distribution and to non-spherical and non-uniform shapesof the particles. In addition, the jet or wet milling methods produceparticles of less than 5 μm. These coarse inhalable particles of lessthan 5 μm may easily reach the lungs by nasal spraying (with a nasalspraying device) or by inhaling (with an inhalation device) and causetiny wounds and scarring to the lungs: each time this happens, it causesa very small amount of irreversible damage. The immediate effect isunnoticeable, but over some periods of time, this can result insignificantly decreased lung capacity, and a number of other healthissues. Therefore, production of the dry powder particles ranging from2-10 μm, particularly less than 5 μm, for the intranasal administrationshould be avoided by all means. The present application providessolution also to this problem by disclosing the method for thepreparation of the active agent particles of the embodiments having aspherical shape with a narrow size distribution (10-30 μm), which aresafe for use in nasal spraying or inhaler devices.

In some embodiments, there is provided a mode of administration of anactive agent by nasal delivery, wherein the active agent has a particlesize more than 10 μm and a narrow size distribution range, the particlesare substantially spherical or ellipsoid and the composition comprisingthis active agent is administered by a spraying with a nasal sprayingdevice or inhaling with an inhaler device.

As described above, the preparation method of the embodiments ischaracterised by the two major steps: the drying, more preferablyspray-drying, of the active agent clear and homogeneous solution, andthen mixing the obtained dry powder with the solid diluent, such aslactose or lactose functional analogue, thereby obtaining thecomposition of the embodiments in a form of dry powder consisting of anactive agent and a solid diluent, said composition having a particlesize ranging from 10 to 30 μm and a spherical shape of the drugparticle. This is in contrast to spray-drying processes described in thepatent documents U.S. Pat. No. 6,462,090, US 20080292713, US 20150010633and US 20160354288, which yield the composite active agent particleswith the particle size less than 5 μm. The spray-drying step in theprocess of the embodiments yields active agent particles larger than 10μm. These particles are then in-situ blended with the solid diluent,such as lactose, to prevent the growth of the particles and theiragglomeration.

The compositions of the embodiments for intranasal administrationcontaining the active compounds, such as analgesics, opioids or triptansmay be used for the fast and efficient pain relief.

To sum up, in some embodiments, there is provided a pharmaceuticalcomposition, wherein the solid diluent is the only excipient, said soliddiluent is used for prevention of active agent aggregation in saidcomposition. In some embodiments, there is provided a pharmaceuticalcomposition, wherein the dry powder particles of the active agent aresubstantially in a spherical form. In some embodiments, atherapeutically effective dose of the pharmaceutical composition of theembodiments may be intranasally administered to a patient in needthereof, wherein the administration is targeted at the uppermost regionof the nasal cavity, thereby resulting in the nose-to-brain (N2B)delivery of the active agent to the brain of the patient, or in thetransmucosal systemic administration. In some embodiments, there isprovided a method of treatment, wherein the administration delivers anentire therapeutically effective dose of at least one active agent toone nostril. In some embodiments, there is provided a method oftreatment, wherein the therapeutically effective dose of at least oneactive agent is administered once daily. In some embodiments, there isprovided a method of treatment, wherein the therapeutically effectivedose of at least one active agent is lower than the therapeuticallyeffective dose of a similar intranasal composition using a non-N2B modeof delivery.

The significantly improved pharmacokinetic profile and superior effectsof the intranasal composition of the present invention on the brain andplasma compared to the oral solution are shown in the in-vivoexperiments (see Example 24, and FIGS. 14-15). The faster onset ofaction and higher drug concentration in plasma were demonstrated for theintranasal powdered composition of the present invention compared to theoral solution. In addition, the faster onset of action and highersustained drug concentration in brain was demonstrated for theintranasal powdered composition of the present invention compared to theoral solution.

EXAMPLES

The following examples illustrate certain features of the presentinvention but are not intended to limit the scope of the presentinvention. In the examples below, the term “ratio” refers to theweight/weight ratio, except the cases where use of other units isspecifically referred to in the text.

Materials

Sumatriptan succinate (from SMS); lactose monohydrate (from MegglePharma); morphine sulphate and oxycodone hydrochloride (from Noramco);naloxone hydrochloride (from Cilag); acetaminophen (from GreenvillePlant); cannabidiol (from THC Pharm); alprazolam (from Centaur);dopamine hydrochloride and insulin (from Sigma-Aldrich); pramipexoledihydrochloride (from LGM Pharma); ondansetron hydrochloride (fromTeva), ethanol and acetone (from BioLab).

Methods

The spray-drying process was carried out using the Mini Spray DryerB-290 of Büchi Labortechnik AG. A magnetic stirrer (Fried Electric) wasplaced under the receiver (receiving chamber), a magnetic bar ofappropriate size was inserted into the receiver, and then the diluentwas added. The liquid feed containing at least one active agent wasprepared by dissolving at least one active compound in the selectedsolvent or mixture of solvents. Quantification was performed using HPLCand a Dionex HPLC instrument. A FEI Quanta-200 Scanning ElectronMicroscope (SEM) equipped with an Everhart-Thornley Detector was used toobtain the images of the spray-dried powder. The accelerating voltage of20 kV was applied to provide magnification from 250 to 10,000 times. Inaddition, an X-ray Element Analysis Detector (Link ISIS, OxfordInstruments, GB) was used to determine the drug and particle identityand their distribution throughout DPI. Particle size was measured usingthe Malvern Mastersizer 3000 series based on the Light Diffractionmethod.

Oxycodone assay in the compositions was performed using Dionex HPLC-PDAinstrument equipped with Chromeleon software. Column: Agilent, ZORBAXSB-CN 4.6×250 mm, 5μ. Mobile phase: 50 mM potassium dihydrogen phosphatebuffer (pH 3.0): acetonitrile (40:60%, v/v). Flow rate: 1.0 mL/min.Column temperature: 25° C. Injection volume: 10 μL.

Oxycodone bio-assay in rat's plasma and brains' oxycodone assay in thecompositions was performed using Dionex HPLC-PDA instrument equippedwith Chromeleon software. Detector: UV at 210 nm. RT of oxycodone: about2.6 min. Diluent: water standard and sample final concentration about 4μg/mL. Column: Agilent, ZORBAX SB-CN 4.6×250 mm, 5μ. Gradient: mobilephase A: 50 mM potassium dihydrogen phosphate buffer (pH 3.0):acetonitrile (45:10%, v/v); mobile phase B: acetonitrile. Flow rate: 1.0mL/min. Column temperature: 25° C. Injection volume: 50 μL. Detection:UV at 210 nm. PDA 200-400 nm. Calibration curve: from 0.1 μg/mL to 4μg/mL prepared by spiking with rat plasma. Quantitative limit: 0.05μg/mL. Internal standard: alprazolam.

Processing Oxycodone HCl in Rat Plasma

1000 plasma (serum) spiked with IS mixed with 600 μL of acetonitrile forprecipitation protein and centrifuged at 14000 rpm for 10 min.Supernatant was dried under nitrogen and reconstituted with 100 μLpotassium dihydrogen phosphate buffer (pH 3.0).

Processing Oxycodone HCl in Rat Brain

Each individual brain tissue was previously weighted and treated by 0.1Mperchloric acid and homogenized. Then it was spiked with IS and mixedwith 14000_, of acetonitrile. After centrifugation at 14000 rpm for 10min, the upper layer was centrifuged again. Supernatant was dried undernitrogen at 40° C. and reconstituted with 100 μL potassium dihydrogenphosphate buffer (pH 3.0).

Example 1: Spray-Drying of Sumatriptan Succinate Solution withoutLactose

This is the reference example for the comparison purposes only.Sumatriptan succinate (12.0 g) was dissolved in 100 ml of deionized (DI)water under stirring at 300 rpm. The resultant clear homogeneoussolution was spray-dried using a Büchi Mini Spray-Dryer with inlet airtemperature of 105° C. and outlet temperature of 62° C., therebyobtaining the dry powder. SEM image (see FIG. 1) showed that theobtained powder was highly aggregated. Large aggregates up to 500microns (μm) are clearly seen on the image.

Example 2: Modification of the Commercial Büchi Labortechnik AGSpray-Dryer

FIG. 2 schematically shows a modified spray dryer of the embodiments. AMini Spray-Dryer B-290 of Büchi Labortechnik AG was modified by: 1.Addition of a magnetic bar into the glass receiver and placing amagnetic stirrer under the continuously rotating glass receiver of thespray-dryer. 2. Selection of a suitable two-fluids spraying nozzle forspraying the solution containing only an active agent (without diluent)into fine droplets suitable for the preparation of 10-30 μm dry powderparticles of the active agent. One of the fluids is the clear andhomogeneous solution of the active agent, and the second fluid is thedrying gas.

Example 3: Sumatriptan Succinate Composition with Lactose Monohydrate

Sumatriptan succinate (2.3 g) was dissolved in a mixture of acetone (12g) and ethanol (12 g) under stirring at 300 rpm. An appropriate sizemagnetic bar was placed in the receiver and lactose monohydrate (2.3 g)was added there. The stirring rate was set at 150 rpm. The clear andhomogeneous solution of the active agent (sumatriptan succinate) wasspray-dried using the Büchi Mini Spray-Dryer with inlet air temperatureof 60° C. and outlet temperature of 55° C., thereby obtaining the drypowder of the active agent, which was further blended with lactosemonohydrate in-situ in the receiver. Stirring was being maintainedduring the entire process. The actual weight of sumatriptan as an activeagent in the obtained sumatriptan/lactose composition was 15.4%. Thecomposition was then mixed with an additional amount of lactose in orderto reach the required 10% active agent (sumatriptan) concentration.

Example 4: SEM Imaging of the Sumatriptan Succinate Composition

High resolution SEM imaging coupled with an X-ray Element AnalysisDetector provides the unique opportunity to identify each individualparticle of a formulation by its chemical content. Using this technique,the particles of sumatriptan succinate containing sulphur (S) atoms canbe differentiated from lactose particles containing carbon (C) andoxygen (O) atoms (without sulphur). FIGS. 3 and 4 show the smallspherical API particles having a narrow size distribution ranging from 5μm to 20 μm, which are dispersed between large lactose polyhedronparticles of ranging from 50 μm to 200 μm. FIG. 3 shows thehigh-resolution image with the 100-μm bar and the elemental analysis ofthe particles. FIG. 4 shows the high-resolution image with the 50 μmbar.

Example 5: Particle Size Analysis of the Sumatriptan SuccinateComposition

The sumatriptan succinate composition prepared in Example 3 wassubjected to the particle size analysis using the Malvern LaserDiffraction instrument (see FIGS. 5 and 6). The following particle sizedistribution was obtained for the sumatriptan succinate composition (seeFIG. 5): D(10)=7 μm, D(50)=79 μm and D(90)=179 μm. Two populations ofthe particles are clearly seen in the figures. The 5-25 μm particles aresumatriptane succinate and the 50-200 μm particles are lactosemonohydrate. The amount of the particles having the size less than 5 μmis about 1%. The particle size distribution of sumatriptan succinatealone was estimated in the range of 0-40 μm (see FIG. 6), and thefollowing results were obtained: D(10)=5.2 μm, D(50)=11.2 μm, D(90)=20.1μm and D(99)=27.1 μm.

Example 6: Acetaminophen (Paracetamol) Composition with LactoseMonohydrate

Acetaminophen (paracetamol) (2.3 g) was dissolved in 65 g ethanol understirring at 300 rpm. An appropriate size magnetic bar was placed in thereceiver and lactose monohydrate (2.3 g) was added there. The stirringrate was set at 150 rpm. The clear and homogeneous solution of the drugwas spray-dried using the Büchi Mini Spray-Dryer with inlet airtemperature of 105° C. and outlet temperature of 56° C., therebyobtaining the dry powder of paracetamol, which was further blendedin-situ with lactose monohydrate. Stirring was being maintained duringthe entire process. Concentration of paracetamol in the composition wasfound to be 23% w/w.

Example 7: SEM Imaging of the Paracetamol Composition

The SEM images (not shown here) show that the small spherical particlesof paracetamol having a narrow size distribution of 2-30 μm aredispersed between the large polyhedron particles of lactose ranging from50 μm to 200 μm.

Example 8: Particle Size Analysis of the Paracetamol Composition

The paracetamol composition prepared in Example 6 was subjected to theparticle size analysis using the Malvern Laser Diffraction instrument.The following particle size distribution was obtained: D(10)=11.6 μm,D(50)=95.4 μm and D(90)=155 μm. Two separate populations of theparticles were clearly seen. The 2-30 μm particles are paracetamol andthe 50-200 μm particles are lactose monohydrate. The percentage of theparticles having the size less than 5 μm was about 7% w/w.

Example 9: Morphine Sulphate Composition with Lactose Monohydrate

Morphine sulphate (2.3 g) was dissolved in a mixture of 18.9 g ethanoland 13.9 g water under stirring at 300 rpm. An appropriate size magneticbar was placed in the receiver and lactose monohydrate (2.3 g) was addedthere. The stirring rate was set at 150 rpm. The clear and homogeneoussolution of the active agent was spray-dried using the Büchi MiniSpray-Dryer with inlet air temperature of 110° C. and outlet temperatureof 86° C., thereby obtaining the dry powder of morphine sulphate, whichwas further blended in-situ with lactose monohydrate in the receiver.Stirring was being maintained during the entire process. Concentrationof morphine sulphate in the composition was about 32% w/w andconcentration of morphine base was about 28% w/w.

Example 10: Particle Size Analysis of the Morphine Sulphate Composition

The morphine sulphate composition prepared in Example 9 was subjected tothe particle size analysis using the Malvern Laser Diffractioninstrument. The following particle size distribution was obtained:D(10)=7.1 μm, D(50)=70.7 μm and D(90)=156 μm. The amount of theparticles having the size less than 5 μm was about 6.6% w/w.

Example 11: Alprazolam Composition with Lactose Monohydrate

Alprazolam (2.3 g) was dissolved in 32.5 g of ethanol under stirring at300 rpm. An appropriate size magnetic bar was placed in the receiver andlactose monohydrate (2.3 g) was added there. The stirring rate was setat 150 rpm. The obtained clear and homogeneous solution of the drug wasthen spray-dried using the Büchi Mini Spray-Dryer with inlet airtemperature of 110° C. and outlet temperature of 86° C., therebyobtaining the dry powder of alprazolam, which was further blendedin-situ with lactose monohydrate in the receiver. Stirring was beingmaintained during the entire process. Concentration of alprazolam in thecomposition was about 33% w/w.

Example 12: Particle Size Analysis of the Alprazolam Composition

The alprazolam—composition prepared in Example 11 was subjected to theparticle size analysis using the Malvern Laser Diffraction instrument.The following particle size distribution was obtained: D(10)=11.7 μm,D(50)=88.0 μm and D(90)=187 μm. The amount of the particles having thesize less than 5 μm was about 0.6% w/w.

Example 13: SEM Imaging of the Alprazolam Composition

FIG. 7 shows the small polyhedron particles of alprazolam having thenarrow size distribution of 5-40 μm, which are dispersed between thelarge polyhedron particles of lactose ranging from 50 μm to 200 μm. FIG.8 shows an X-ray analysis of the obtained alprazolam polyhedronparticles, where the large particles containing C and 0 atoms only mustbe lactose, and the small particles additionally containing Cl atomsmust be alprazolam.

Example 14: Oxycodone Hydrochloride Composition with Lactose Monohydrate

Oxycodone hydrochloride (2.3 g) was dissolved in 9.9 g of ethanol understirring at 300 rpm. An appropriate size magnetic bar was placed in thereceiver and lactose monohydrate (2.3 g) was added there. The stirringrate was set at 150 rpm. The clear and homogeneous solution of the drugwas spray-dried using the Büchi Mini Spray-Dryer with inlet airtemperature of 90° C. and outlet temperature of 56° C., therebyobtaining the dry powder of the active agent, which was further blendedin-situ with lactose monohydrate in the receiver. Stirring in thereceiver was being maintained during the entire process. Concentrationof oxycodone hydrochloride in the composition was about 41% w/w andconcentration of oxycodone base was about 37% w/w.

Example 15: SEM Imaging of the Oxycodone Hydrochloride Composition

FIG. 9 shows the small spherical particles of oxycodone hydrochloridehaving the narrow size distribution of 3-30 μm, which are dispersedbetween the large polyhedron particles of lactose ranging from 50 μm to200 μm.

Example 16: Particle Size Analysis of the Oxycodone HydrochlorideComposition

The oxycodone hydrochloride composition prepared in Example 14 wassubjected to the particle size analysis using the Malvern LaserDiffraction instrument (see FIG. 10). The following particle sizedistribution was obtained: D(10)=7.7 μm, D(50)=64.4 μm and D(90)=141 μm.The amount of the particles having the size less than 5 μm was about 3%w/w.

Example 17: Dopamine Hydrochloride Composition with Lactose Monohydrate

Dopamine hydrochloride (2.3 g) was dissolved in a mixture of 7.0 gethanol, 7.0 g acetone and 9.0 g water under stirring at 300 rpm. Anappropriate size magnetic bar was placed in the receiver and lactosemonohydrate (2.3 g) was added there. The stirring rate was set at 150rpm. The obtained clear and homogeneous solution of the active agent wasspray-dried using the Büchi Mini Spray-Dryer with inlet air temperatureof 95° C. and outlet temperature of 65° C., thereby obtaining the drypowder of dopamine hydrochloride, which was further blended in-situ withlactose monohydrate in the receiver. Stirring in the receiver was beingmaintained during the entire process. Concentration of dopaminehydrochloride in the composition was about 37% w/w and concentration ofdopamine base was about 26% w/w.

Example 18: Particle Size Analysis of the Dopamine HydrochlorideComposition

The dopamine hydrochloride composition prepared in Example 17 wassubjected to the particle size analysis using the Malvern LaserDiffraction instrument. The following particle size distribution wasobtained: D(10)=8.0 μm, D(50)=74.9 μm and D(90)=147 μm. The amount ofthe particles having the size less than 5μ was about 3.5% w/w.

Example 19: Insulin Composition with Lactose Monohydrate

5 ml of insulin saline (sodium chloride) solution containing 500 IU ofinsulin was mixed with 7 ml of water under stirring at 300 rpm. Anappropriate size magnetic bar was placed in the receiver and lactosemonohydrate (2.3 g) was added there. The stirring rate was set at 150rpm. The obtained clear and homogeneous solution of insulin wasspray-dried using the Büchi Mini Spray-Dryer with inlet air temperatureof 90° C. and outlet temperature of 56° C., thereby obtaining theinsulin dry powder, which was further blended in-situ with lactosemonohydrate in the receiver. Stirring in the receiver was beingmaintained during the entire process.

Example 20: SEM Imaging of the Insulin Composition

FIG. 11 shows the small spherical particles of insulin-sodium chloridehaving the size of 5-7 μm laid on the surface of the large lactosepolyhedron particles having the size above 100 μm. The elementalanalysis shown on the FIG. 12 confirms that the particles include sodiumchloride and sulphur, which is a clear indication that these particlesare insulin.

Example 21: Particle Size Analysis of the Insulin Composition

The insulin composition prepared in Example 19 was subjected to theparticle size analysis using the Malvern Laser Diffraction instrument.The following particle size distribution was obtained (see FIG. 13):D(10)=57.4 μm, D(50)=97.3 μm and D(90)=151 μm. The amount of theparticles having the size less than 5 μm was about 0.3% w/w.

Example 22: Intranasal Drug Delivery

Aptar Unit-Dose Powder disposable devices were filled with thesumatriptan succinate composition prepared in Example 1. These deviceswere assembled according to the company guideline. Each device contained10 mg of powder including 1 mg of sumatriptan succinate (100 mg/g as alabeled claim). Ten devices were packed, activated, and the powderdelivered upon actuation of each device was collected and weighed. Theweights (mg) of the delivered powder dose from the ten devices are shownin Table 1 below. Uniformity of the delivered dose (mg/g) from each ofthe ten devices, measured with an HPLC instrument according to thecompany protocol, is also shown in Table 1. In addition, Table 1contains the data from the two devices that were stored for 6 months(“6M” in the table) at 40° C. and 75 RH.

TABLE 1 Delivered dose and uniformity of the delivered dose SumatriptanSample weight, base content, Sample name mg mg/g Composition 1-1 10.04103.40 Composition 1-2 10.05 93.51 Composition 1-3 10.07 108.63Composition 1-4 9.94 103.28 Composition 1-5 10.07 91.54 Composition 1-610.05 104.63 Composition 1-7 10.04 99.15 Composition 1-8 10.06 122.88Composition 1-9 10.03 109.75 Composition 1-10 10.00 106.86 AVG 10.03104.06 RSD, % 0.4 8.5 Composition 1-11 (6M) 9.79 97.42 Composition 1-12(6M) 9.82 104.95 AVG 9.8 101.2 RSD, % 0.3 7.4

Example 23: Plume Geometry and Spray Pattern

Evaluation of the Plume Geometry and Spray Pattern of the compositionsactuated from the Aptar Unit-Dose Powder (UDP) disposable devices wasconducted using FDA's CMC Guidance⁹. Three replicates of eachcomposition either fresh prepared or stored were tested for: Plumeangle)(°; Plume width at 6 cm; Plume length (cm) and duration time (ms).Results from two spray-patterns (3 and 6 cm) were recorded providingdetails on diameter min (cm), diameter max (cm), area and ovality ratio.An appropriate high-resolution visualisation technique was used. ⁹NasalSpray and Inhalation Solution, Suspension, and Spray DrugProducts—Chemistry, Manufacturing, and Controls Documentation, July2002.

Example 24: PK Evaluation Following Single Intranasal or Oral DoseAdministration of Oxycodone in Rats

The objective of this study was to determine the pharmacokinetic profileof oxycodone following single administration of oral solution ofoxycodone hydrochloride in PBS buffer and intranasal (IN) powder ofoxycodone composition of invention described in the Example 14. Thedosing was done at 10 mg/kg (2 mg per rat) by oral gavage or by modifiedintranasal Aptar device to 12 SD male rats for each rout ofadministration.

Study variables and end points were measured as following:

-   -   1) Morbidity and Mortality—daily.    -   2) Body weight—was measured during acclimation and before Test        Item administrations.    -   3) Clinical sign observation—animals were observed for toxic        signs after dosing.    -   4) Blood withdrawal—blood samples were collected at baseline (24        hours before dosing), 5, 15, 40, 60, 90, 120, 240 and 420        minutes after administration (three rats per bleeding time        points for each Rout of administration).    -   5) Brains were removed after bleeding at time points: 15, 60,        120 and 420 minutes (three rats at each time point for each Rout        of administration)

T_(max), C_(max) and AUC_(t) (area under the concentration-time curvefrom zero up to a definite time t, the parameter that is used as anindex of the drug exposure of the body, when referred to the plasma druglevels, and is closely dependent on the drug amount that enter into thesystemic circulation).

The brain PK parameters were measured in the similar manner and reportedas drug concentration in the ml of homogenated brain tissues. Thesesamples were analysed for oxycodone content by a HPLC-UV method. Theobtained plasma pharmacokinetic parameters of the oral and theintranasal products are shown in Table 2 and FIG. 14.

TABLE 2 Oxycodone pharmacokinetic parameters in rat's plasma C_(max IN)/AUC_(IN)/ Oxycodone AUC₀₋₄₂₀ T_(max) C_(max) C_(max ORAL) AUC_(ORAL)Product (μg*min/ml) (min) (μg/ml) (%) (%) Intranasal 4.23 5 1.88 2.981.49 powder Oral gavage 2.83 60 0.63

As can be seen from the Table 2 and FIG. 14, the C. value is almost 3folds higher, while the AUS value is increased at 1.5 folds uponintranasal administration. The comparative value of T_(max) of 5 minversus 60 min demonstrates the extremely fast onset of action followingintranasal administration of oxycodone. The very fast nasal transmucosalabsorption is manifested by the immediate increase in plasma oxycodoneconcentration, since it is observed following the administering of onlythe intranasal powder. The initial increase is later followed by thesecond peak of 60 min, exhibiting the gastrointestinal absorption, whichis seen both in the intranasal and oral oxycodone formulations.

As the intranasal formulation has been reported to have a more rapidonset of effect^(10,11), which is attributed to the rapid increase inblood levels, the present results suggest that oxycodone intranasalpowder also has a fast pain relief onset of action. ¹⁰Mohammad Obaidi etal., Improved Pharmacokinetics of Sumatriptan with Breath Powered™ NasalDelivery of Sumatriptan Powder, Headache, 2013, vol. 53, pp1323-1333¹¹Fuseau E et al., Clinical pharmacokinetics of intranasalsumatriptan, Clin Pharmacokinet., 2002, vol. 41(11), pp 801-811.

The obtained brain pharmacokinetic parameters of the oral and theintranasal products are shown in Table 3 and FIG. 15.

TABLE 3 Oxycodone pharmacokinetic parameters in rat's brains C_(max IN)/AUC_(IN)/ Oxycodone AUC₀₋₄₂₀ T_(max) C_(max) C_(max ORAL) AUC_(ORAL)Product (μg*min/ml) (min) (μg/ml) (%) (%) Intranasal 29.03 420 6.6312.05 11.52 powder Oral gavage 2.52 120 0.55

As can be seen from the Table 3 and FIG. 15, the C_(max) value is 12folds higher, while the AUS value is increased 11.5 times uponintranasal administration. The T_(max) value of 420 min versus 120 mindemonstrates the sustained action of oxycodone following intranasaladministration. However, the concentrations of the drug after 15 minwere found to be 2.94 μg/ml and 0.23 μg/ml for intranasal and oralroute, respectively. This is the clear evidence that the immediate andhuge increase of oxycodone concentration in brain is a result of thedirect drug delivery to the brain via intranasal route exclusively. Theoxycodone peak in brain of 120 min following the gastrointestinalabsorption is typical for oral oxycodone formulations.

The rapid onset and prolonged action of oxycodone demonstrated in thepresent application is a significant breakthrough in the post-surgerypain management of patients. Both oral and intranasal formulations werewell tolerated. No toxic signals or any abnormal effects were observed.

1. A pharmaceutical composition in a form of dry powder for intranasaladministration to a patient in need thereof, comprising solid particlesof at least one active agent and solid particles of a diluent, whereinsaid pharmaceutical composition is free of excipients other than thesolid diluent, and has at least 90% of the particles of said at leastone active agent with a mean particle size ranging from 10 microns to 30microns, and less than 10% of the particles of said at least one activeagent with a mean particle size equal to or below 5 microns.
 2. Thepharmaceutical composition of claim 1, wherein the mean particles sizeof said diluent is 30-200 microns.
 3. The pharmaceutical composition ofclaim 1, wherein the at least one active agent is selected fromanalgesics, anti-emetics, anti-inflammatory agents, anti-bacterialagents, anti-viral agents, anti-depressants, anti-epileptics,anti-hypertensive agents, anti-migraine agents, anti-neoplastic agents,chemotherapeutic drugs, immunosuppressants, anti-Parkinsonian agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, beta-blockers,corticosteroids, COX-2 inhibitors, opioid analgesics, proteaseinhibitors, hormones, peptides, antibodies, chemotherapy agents andmixtures thereof.
 4. The pharmaceutical composition of claim 3, whereinthe at least one active agent is selected from sumatriptan succinate,zolmitriptan salts, naratriptan, rizatriptan, almotriptan, eletriptan,frovatriptan, bupivacaine, fibroblast growth factor, cephalexin,lidocaine, clobazame, midazolam, alprazolam, diazepine, lorazepam,dexmedetomidine, monosialoganglioside, cocaine, insulin, glucagon,oxytocin, fentanyl, sulfentanil, diamorphine, ketamine, apomorphine,buprenorphine, morphine sulphate, oxycodone hydrochloride, butorphanol,NSAIDs, paracetamol, benzodiazepines, dopamine, pramipexole, rasagiline,rogitine, ondansetron, granisetron, metoclopramide, naloxone,naltrexone, atropine, adrenaline, cannabis active compounds,epinephrine, isosorbide dinitrate, obitoxine, dexmedetomidine,metochlorpramide, L-dopa, nicotine, sildenafil, nafarelin, dobutamine,phenylephrine, tramazoline, xylometazoline, tramadol, methacholine,ipratropium, scopolamine, propranolol, verapamil, hydralazine,nitroglycerin, clofilium tosylatecannabis active compounds andpharmaceutically acceptable salts, isomers, and mixtures thereof.
 5. Thepharmaceutical composition of claim 1, wherein the diluent is selectedfrom lactose monohydrate, lactose or a lactose functional analogue. 6.The pharmaceutical composition of claim 5, wherein said diluent has themean particle size of 30-200 microns.
 7. The pharmaceutical compositionof claim 6, wherein said diluent has the mean particle size of 50-150microns.
 8. The pharmaceutical composition of claim 5, wherein thelactose functional analogue is selected from cellulose and derivatives,starch and derivatives dextrose, sorbitol, mannitol, maltitol, xylitolor mixtures thereof.
 9. The pharmaceutical composition of claim 8,wherein said lactose functional analogue has the mean particle size of50-150 microns.
 10. The pharmaceutical composition of claim 1, whereinthe diluent is the only excipient for preventing aggregation of the drypowder particles of the active agent and preserving their original sizeand shape in said composition.
 11. The pharmaceutical composition ofclaim 1, wherein the dry powder particles of the active agent aresubstantially in a spherical form.
 12. The pharmaceutical composition ofclaim 1 for use in intranasal administration to a patient in needthereof, wherein the administration is targeted at the uppermost regionof the nasal cavity, thereby resulting in the nose-to-brain (N2B)delivery of the active agent to the brain of the patient.
 13. Thepharmaceutical composition of claim 1 for use in intranasaladministration to a patient in need thereof, wherein the administrationis targeted at the uppermost region of the nasal cavity, therebyresulting in the transmucosal systemic administration.
 14. An apparatusfor the preparation of the pharmaceutical composition of claim 1 in adry powder form, said apparatus comprising: a) A spray-drying chamber[1] capable of spray-drying a clear and homogeneous solution of at leastone active agent to obtain dry powder particles of said at least oneactive agent in a moist air, said solution being free of diluent; b) Acyclone separator [2] capable of receiving said dry powder particles andthe moist air stream from said spray-drying chamber [1], separating saidparticles from the moist air through vortex separation, exhausting theair and transferring the separated particles to a receiving chamber [3]through a bag filter; and c) The receiving chamber [3] pre-filled with adiluent and adapted for receiving the separated dry powder particlesfrom the cyclone separator [2], mechanically stirring and homogenisingsaid particles with the diluent to obtain the pharmaceutical compositionin the dry powder form of the embodiments; wherein said diluent iscapable of colliding and continuous in-situ blending with the particlesduring the stirring in the receiving chamber [3], thereby preventingtheir aggregation and preserving their original size and shape.
 15. Themethod for the preparation of the pharmaceutical composition of claim 1in a dry powder form, said method comprising: A. Preparing a clear andhomogeneous solution of at least one active agent in an organic solventor solvent mixture, in a solvent-water or water miscible solventmixture, or in water. B. Filling the receiving chamber [3] with adiluent and continuously stirring the diluent in the receiving chamber[3]; C. Streaming the solution prepared in step (A) together with hotair to the spray-draying chamber [1], spray-drying the solution in thespray-drying chamber [1] to obtain dry powder particles of said at leastone active agent in a moist air, and transferring the obtained drypowder particles and the moist air stream to the cyclone separator [2];D. Separating said particles from the moist air through vortexseparation in the cyclone separator [2], exhausting the air andtransferring the separated particles to the receiving chamber [3]through a bag filter; E. Stirring and homogenising said particlesreceived from step (D) with the diluent in the receiving chamber [3] toobtain the pharmaceutical composition of the embodiments in the drypowder form; wherein said diluent is capable of colliding and continuousin-situ blending with the particles during the stirring in the receivingchamber [3], thereby preventing their aggregation and preserving theiroriginal size and shape; and F. Adding diluent and additionally mixingof the pharmaceutical composition obtained in step (E) with anadditional amount of the diluent to achieve a desired activeagent-to-diluent ratio in said pharmaceutical composition.